Additional Biomarkers Are Needed to Inform ADC Selection in NSCLC

Antibody-drug conjugates (ADCs) are reshaping the treatment landscape in lung cancer; however, additional study is needed to better define biomarkers to help personalize ADC treatment for patients, according to Benjamin P. Levy, MD.¹

“ADCs represent a novel therapy strategy for patients,” Levy said in a presentation during the 20th Annual New York Lung Cancers Symposium®. “We need [to do] a lot of work preclinically and clinically to understand how these drugs work. Refining and defining biomarkers are going to be critical tropes; this is just the beginning of the story. We need more sophisticated ways to do this. The future is bright, and I look forward to seeing how these drugs unfold in our clinic with future studies.”

Levy is a thoracic medical oncologist and the clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, as well as an associate professor of oncology at Johns Hopkins in Washington, DC.

What are the latest data with HER2-directed ADCs?

Levy began his presentation by discussing HER2-targeted ADCs in the lung cancer space, most notably fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). T-DXd was granted accelerated approval by the FDA in August 2022 for the treatment of adult patients with HER2-mutated unresectable or metastatic non–small cell lung cancer (NSCLC) who received a prior systemic therapy. The regulatory decision distinguished T-DXd as the first agent to gain FDA approval in patients with HER2-mutated NSCLC.²

The approval was supported by data from the phase DESTINY-Lung02 trial (NCT04644237), which Levy noted evaluated the agent for the treatment of patients with pretreated HER2-mutated NSCLC at 2 doses: 5.4 mg/kg (n = 102) or 6.4 mg/kg (n = 50) once every 3 weeks. Findings from the final analysis of the DESTINY-Lung02 trial, which were published in the Journal of Thoracic Oncology, showed that patients who received T-DXd at the 5.4-mg/kg and 6.4-mg/kg dose levels experienced confirmed overall response rates (ORRs) of 50.0% (95% CI, 39.9%-60.1%) and 56.0% (95% CI, 41.3%-70.0%), respectively.³

“At the 6.4-mg/kg dose we didn't see much higher response rates [compared with the 5.4 mg/kg dose], and we saw a bit more interstitial lung disease [ILD],” Levy noted. “We're going to find out, hopefully soon, from [the phase 3] DESTINY-Lung04 trial [NCT05048797] whether we can push this drug into the first-line setting.”

Levy added that T-DXd also received FDA approval for the treatment of patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options in 2024.⁴ “In [the phase 2 DESTINY-PanTumor02 study (NCT04482309)], there weren't a lot of patients [with] lung cancer, nevertheless, this did get a pan-tumor approval for patients with HER2 overexpression in multiple different tumor types.”

However, data from the phase 1b DESTINY-Lung03 trial (NCT04686305) presented during the 2024 IASLC World Conference on Lung Cancer showed that the confirmed ORR was 56.3% (95% CI, 29.9%-80.3%) in patients with metastatic NSCLC with a HER2 IHC of 3+ (n = 16).⁵ The median progression-free survival (PFS) and overall survival (OS) were 6.9 months (95% CI, 5.3-17.9) and 16.4 months (95% CI, 6.8-not estimable), respectively.

Another promising HER2-targeted ADC in NSCLC is trastuzumab rezetecan (also known as SHR-A1811), which was evaluated for the treatment of patients with advanced HER2-mutated NSCLC in the phase 2 HORIZON-Lung trial (NCT04818333).⁶ Findings from HORIZON-Lung, which were published in Lancet Oncology, showed that patients who received the agent (n = 94) achieved a confirmed ORR of 73% (95% CI, 63.3%-82.0%) and a median PFS of 11.5 months (95% CI, 9.9-not reached); OS data are still immature.

“This novel ADC is approved in China, but whether this will come to the United States is unclear,” Levy noted. “I want to create some awareness that there are other HER2-directed ADCs that have meaningful activity and safety.”

Which TROP2 ADCs are changing the treatment landscape in lung cancer?

As of November 2025, Datopotamab deruxtecan-dlnk (dato-DXd; Datroway) is the only FDA-approved TROP2-targeted ADC for lung cancer.⁷ The agent earned accelerated approval from the FDA in June 2025 in adult patients with locally advanced or metastatic EGFR-mutated NSCLC who received prior EGFR-targeted and platinum-based chemotherapy.

Findings from a pooled analysis of the phase TROPION-Lung05 (NCT04484142) and TROPION-Lung01 (NCT04656652) studies showed that patients with EGFR-mutated NSCLC who received the agent (n = 117) experienced a confirmed ORR of 43% (95% CI, 34%-52% and a median DOR of 7.0 months (95% CI, 4.2-9.8).⁸ The median PFS and OS were 5.8 months (95% CI, 5.4-8.2) and 15.6 months (95% CI, 13.1-19.0), respectively.

“We need to be mindful of safety with Dato-DXd,” Levy said. “We have the traditional cytotoxic chemotherapy adverse effects [AEs] such as alopecia and the gastrointestinal toxicities as well as cytopenias, but we need to remember the AEs of special interest, [including] stomatitis, ocular surface events and ILD.”

What MET-targeted ADCs are available?

Telisotuzumab vedotin-tllv (Emrelis) is a MET-directed ADC that was granted accelerated approval by the FDA in May 2025 for the treatment of patients with locally advanced or metastatic, nonsquamous NSCLC with high c-MET protein overexpression (≥ 50% of tumor cells with strong [IHC 3+] staining who received a prior systemic therapy.⁹ The approval was supported by data from the phase 2 LUMINOSITY study (NCT03539536).

Primary findings from LUMINOSITY showed that patients with c-MET–overexpressing disease (n = 168) experienced an ORR of 28.6% (95% CI, 21.7%-36.2%).¹⁰ The median DOR was 7.2 months (95% CI, 5.5-11.0). The median PFS and OS were 5.6 months (95% CI, 4.6-6.8) and 14.2 months (95% CI, 9.9-16.4), respectively, among patients previously treated with platinum-based chemotherapy.¹¹

“We need to remember that telisotuzumab vedotin has a different payload [compared with the other ADCs],” Levy noted. “Peripheral sensory neuropathy and edema were seen in this study, as well as pneumonitis, although rare, as well as keratitis and ocular events.”

What potential biomarkers could inform ADC selection?

Levy concluded his presentation by discussing findings with potential biomarkers that could help oncologists individualize ADC treatment for patients. “We’re trying to understand how these drugs work, what the biomarkers are, and where they should be leveraged,” he explained. He added that the normalized membrane ratio of (NMR) of TROP2 per quantitative continuous scoring could represent a potential biomarker of interest to inform treatment with Dato-DXd.

Findings from an analysis of TROPION-Lung01 showed that patients with TROP2-positive disease per QCS-NMR who received dato-DXd (n = 107) achieved an ORR of 32.7% and a median PFS of 6.9 months.¹² Comparatively, patients with a negative TROP2 QCS-NMR who received the agent (n = 65) experienced an ORR of 16.9% and a median PFS of 2.9 months.

“This is an artificial intelligence–assisted way to look at a computational pathology approach,” Levy explained. “Whole slides are stained, you create a digital image of the slide, and then you have a training model that will accurately read where TROP2 expression is occurring in every single cell. In this model, they're more interested in the expression of TROP2 inside the cell vs how it's expressed on the cell surface. It seemed like this was predictive of response to Dato-DXd.”

References

1. Levy BP. Antibody drug conjugates: where we’re at and which way we are going. Presented at: 20th Annual New York Lung Cancers Symposium®; November 15, 2025; New York, NY.
2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. Updated August 16, 2022. Accessed November 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
3. Jänne PA, Goto Y, Kubo T, et al. final analysis results and patient-reported outcomes from DESTINY-Lung02-a dose-blinded, randomized, phase 2 study of trastuzumab deruxtecan in patients with HER2-mutant metastatic NSCLC. J Thorac Oncol. Published online July 30, 2025. doi:10.1016/j.jtho.2025.07.129
4. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed November 15, 2025.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
5. Planchard D, Kim HR, Suksombooncharoen T, et al. Trastuzumab deruxtecan monotherapy in pretreated HER2-overexpressing nonsquamous non-small cell lung cancer: DESTINY-Lung03 part 1. Presented at: IASLC 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA16.05.
6. Li Z, Wang Y, Sun Y, et al. Trastuzumab rezetecan, a HER2-directed antibody-drug conjugate, in patients with advanced HER2-mutant non-small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study. Lancet Oncol. 2025;26(4):437-446. doi:10.1016/S1470-2045(25)00012-9
7. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025.Accessed November 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer
8. Ahn MJ, Lisberg A, Goto Y, et al. A pooled analysis of datopotamab deruxtecan in patients with EGFR-mutated NSCLC. J Thorac Oncol. 2025;20(11):1669-1682. doi:10.1016/j.jtho.2025.06.002
9. FDA grants accelerated approval to telisotuzumab vedotin-tllv for NSCLC with high c-Met protein overexpression. FDA. May 14, 2025. Accessed November 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression
10. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-met protein–overexpressing advanced nonsquamous EGFR-wildtype non–small cell lung cancer in the phase II LUMINOSITY trial. J Clin Oncol. 2024;42(supp; 25):3000-3011. doi:10.1200/JCO.24.00720
11. Girad N, Camidge DR, Bar J, et al. 18P: Telisotuzumab vedotin monotherapy in patients with previously treated c-Met protein–overexpressing nonsquamous EGFR wildtype advanced NSCLC: updated analysis of the LUMINOSITY trial. J Thorac Oncol. 2025;20(suppl 1):S21-S23. doi:10.1016/S1556-0864(25)00213-8
12. Garassion MC, Sands J, Paz-Ares L, et al. Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung 01. J Thorac Oncol. 2024;19(10):S2-S3. doi:10.1016/j.jtho.2024.09.015